Compositions, methods, and systems for the synthesis and use of imaging agents

Abstract

The present invention relates to systems, compositions, and methods for the synthesis and use of imaging agents, or precursors thereof. An imaging agent precursor may be converted to an imaging agent using the methods described herein. In some cases, the imaging agent is enriched in 18F. In some cases, an imaging agent may be used to image an area of interest in a subject, including, but not limited to, the heart, cardiovascular system, cardiac vessels, brain, and other organs. In some embodiments, methods and compositions for assessing perfusion and innervation mismatch in a portion of a subject are provided.

1 - 373 . (canceled) 
     
     
         374 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein: 
       
         
           
           
               
               
           
         
         L is selected from —OCH 2 CH 2 —, —NH 2 CH 2 CH 2 —, —CH═N—, 
         R 1  is: 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of R B  is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen-protecting group, provided at least two R B  are hydrogen; 
         R 2  and R 6  are hydrogen; 
         each of R 3 , R 4  and R 5  is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A2 ) 2 , —SR A1 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)SR A1 , —C(═O)N(R A2 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A2 ) 2 , —NR A2 C(═O)R A2 , —NR A2 C(═O)OR A1 , —NR A2 C(═O)SR A1 , —NR A2 C(═O)N(R A2 ) 2 , —SC(═O)R A1 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A2 ) 2 , —C(═NR A2 )R A1 , —C(═NR A2 )OR A1 , —C(═NR A2 )SR A1 , —C(═NR A2 )N(R A2 ) 2 , —OC(═NR A2 )R A1 , —OC(═NR A2 )OR A1 , —OC(═NR A2 )SR A1 , —OC(═NR A2 )N(R A2 ) 2 , —NR A2 C(═NR A2 )R A2 , —NR A2 C(═NR A2 )OR A1 , —NR A2 C(═NR A2 )SR A1 , —NR A2 C(═NR A2 )N(R A2 ) 2 , —SC(═NR A2 )R A1 , —SC(═NR A2 )OR A1 , —SC(═NR A2 )SR A1 , —SC(═NR A2 )N(R A2 ) 2 , —C(═S)R A1 , —C(═S)OR A1 , —C(═S)SR A1 , —C(═S)N(R A2 ) 2 , —OC(═S)R A1 , —OC(═S)OR A1 , —OC(═S)SR A1 , —OC(═S)N(R A2 ) 2 , —NR A2 C(═S)R A2 , —NR A2 C(═S)OR A1 , —NR A2 C(═S)SR A1 , —NR A2 C(═S)N(R A2 ) 2 , —SC(═S)R A1 , —SC(═S)OR A1 , —SC(═S)SR A1 , —SC(═S)N(R A2 ) 2 , —S(═O)R A1 , —SO 2 R A1 , —NR A2 SO 2 R A1 , —SO 2 N(R A2 ) 2 , —CN, —SCN, or —NO 2 ; or any two adjacent R 3 , R 4  and R 5  are joined to form an optionally substituted or unsubstituted carbocyclic, heterocyclic, aryl, or heteroaryl ring; 
         each occurrence of R A1  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each occurrence of R A2  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, or two R A2  groups are joined to form an optionally substituted heterocyclic ring; and 
         wherein R 4  is substituted with an imaging moiety selected from the group consisting of  18 F,  76 Br, and  124 I; or is associated with an imaging moiety selected from the group consisting of  64 Cu,  89 Zr,  99m Tc, and  111 In through a chelator; or is  124 I. 
       
     
     
         375 . The compound of  claim 374 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         376 . The compound of  claim 374 , wherein R 4  is alkyl substituted with the imaging moiety. 
     
     
         377 . The compound of  claim 374 , wherein R 4  is alkoxy substituted with the imaging moiety. 
     
     
         378 . The compound of  claim 377 , wherein R 4  is substituted with  18 F. 
     
     
         379 . The compound of  claim 377 , wherein R 4  is —OCH 2 F, —OCH 2 CH 2 F, —OCH 2 CH 2 CH 2 F, or —OCH 2 CH 2 CH 2 CH 2 F, wherein F is isotopically enriched with  18 F. 
     
     
         380 . The compound of  claim 374 , wherein R 4  is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein n is an integer between 0 and 6, inclusive; and m is an integer between 0 and 6, inclusive. 
     
     
         381 . The compound of  claim 380 , where R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         382 . The compound of  claim 374 , wherein R 5  is hydrogen. 
     
     
         383 . The compound of  claim 374 , wherein R 3  and R 5  are hydrogen. 
     
     
         384 . The compound of  claim 374 , wherein R 3  is hydrogen. 
     
     
         385 . The compound of  claim 374 , wherein R 3  is halogen. 
     
     
         386 . The compound of  claim 374 , selected from: 
       
         
           
           
               
               
           
         
       
       and salts thereof, wherein each F is enriched with  18 F. 
     
     
         387 . A pharmaceutical composition comprising a compound of  claim 374 , or a salt thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
         388 . A method of imaging cardiac innervation, comprising administering an effective amount of a compound of  claim 374 , or a salt thereof, to a subject, and detecting radiation emitted by the compound; and forming an image therefrom. 
     
     
         389 . A method of imaging a subject, comprising administering a compound of  claim 374  or a salt thereof, to the subject, and acquiring at least one image of a portion of the subject. 
     
     
         390 . A method of detecting norepinephrine transporter (NET) in a portion of a subject, comprising administering a compound of  claim 374 , or a salt thereof, to the subject, and acquiring at least one image of the portion of the subject, wherein the image detects NET in the subject. 
     
     
         391 . A method of selecting an antiarrhythmic agent and/or determining the dose of an antiarrhythmic agent for administration to a subject, the method comprising administering to a subject the compound of  claim 374 , or a salt thereof, acquiring at least one image of a portion of the subject; and selecting the antiarrhythmic agent and/or determining the dose of an antiarrhythmic agent for administration to a subject based on the at least one first image. 
     
     
         392 . The method of  claim 391 , wherein a reduced dose of an antiarrhythmic agent that induces electrophysiological changes in a subject's heart is prescribed based on the at least one first image indicating presence of cardiac denervation. 
     
     
         393 . A method comprising administering to a subject the compound of  claim 374 , or a salt thereof, acquiring at least one image of a portion of the subject; and identifying
 (i) a subject to be treated with an antiarrhythmic agent that does not induce electrophysiological changes in the heart of the subject based on presence of cardiac denervation in the image;   (ii) a subject to be treated with a reduced dose of an antiarrhythmic agent that induces electrophysiological changes in the heart of the subject based on presence of cardiac denervation in the image; and/or   (iii) a subject in need of a dose reduction of an antiarrhythmic agent that induces electrophysiological changes in the heart of the subject based on presence of cardiac denervation in the image.